Pharmaceutical composition, methods for treating and uses thereof

ABSTRACT

The present invention relates to methods for treating or preventing chronic kidney disease and cardiovascular disease in patients with chronic kidney disease comprising administering empagliflozin to the patient.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to methods for treating or preventingchronic kidney disease and cardiovascular disease in patients withchronic kidney disease.

BACKGROUND OF THE INVENTION

Chronic kidney disease (CKD), also known as chronic renal disease, is aprogressive loss in renal function over a period of months or years. Thesymptoms of worsening kidney function are non-specific, and chronickidney disease is often diagnosed as a result of screening of peopleknown to be at risk of kidney problems. CKD is a highly prevalentdisease, afflicting more than one out of ten individuals worldwide.

Chronic kidney disease may be identified by a blood test, for examplefor creatinine. Higher levels of creatinine indicate a lower glomerularfiltration rate and as a result a decreased capability of the kidneys toexcrete waste products.

CKD has been classified into 5 stages, where stage 1 is kidney damagewith normal GFR (mL/min/1.73 m²) of ≥90; stage 2 is kidney damage with amild decrease in GFR (GFR 60-89); stage 3 is a moderate decrease in GFR(GFR 30-59); stage 4 is a severe decrease in GFR (GFR 15-29); and stage5 is kidney failure (GFR<15 or dialysis). Stage 5 CKD is often calledEnd Stage Renal Disease (ESRD) and is synonymous with the now outdatedterms chronic kidney failure (CKF) or chronic renal failure (CRF).

Albuminuria can also be a sign of kidney disease. Albuminuria has beenclassified into 3 categories, where category A1 reflects no albuminuriawith albumin normal to mildly increased; category A2 which reflectsmicroalbuminuria with albumin moderately increased; category A3 whichreflects macroalbuminuria with albumin severely increased.

There is no specific treatment unequivocally shown to slow the worseningof chronic kidney disease and severe CKD requires renal replacementtherapy, which may involve a form of dialysis, but ideally constitutes akidney transplant.

Since many CKD patients will die due to a cardiovascular event (CV)event before reaching ESRD, reducing CV risk is another consideration intreatment.

Therefore, there is an unmet medical need for methods, medicaments andpharmaceutical compositions able to slow the worsening or progression ofchronic kidney disease and reduce the risk of CV events in patients, inparticular patients with chronic kidney disease.

SUMMARY OF THE INVENTION

The present invention provides a method of treating or slowing theprogression of chronic kidney disease in a patient with chronic kidneydisease, the method comprising administering empagliflozin to thepatient. In one aspect, the method additionally reduces the risk ofcardiovascular death in the patient. In one aspect, the methodadditionally reduces the risk of all-cause mortality in the patient. Inone aspect, the method additionally reduces the risk of all-causehospitalization in the patient. In a further aspect, the patient hasmoderately or severely decreased renal function or elevated albuminurialevels, for example ≥200 mg/g.

In one aspect, the present invention also provides a method for reducingthe risk of chronic kidney disease, the method comprising administeringempagliflozin to the patient. In one aspect, the method additionallyreduces the risk of cardiovascular death in the patient. In one aspect,the method additionally reduces the risk of all-cause mortality in thepatient. In one aspect, the method additionally reduces the risk ofall-cause hospitalization in the patient. In a further aspect, thepatient has moderately or severely decreased renal function or elevatedalbuminuria levels, for example ≥200 mg/g.

In one aspect, the patient has an eGFR≥20 to <45 mL/min/1.73 m². In oneaspect, the patient has an eGFR≥20 mL/min/1.73 m² and a urinaryalbumin-to-creatine ratio (UACR)≥200 mg/g. In one aspect, the patienthas an eGFR≥45 and <90 ml/min/1.73 m² and a urinary albumin-to-creatineratio (UACR)≥200 mg/g.

In one aspect, the patient is treated with a RAAS inhibitor(Renin-Angiotensin-Aldosterone System). In one aspect, the patient istreated with an Angiotensin-Converting Enzyme (ACE) inhibitor and/or anangiotensin II receptor blocker (ARB).

In one aspect, the patient is on standard of care according tolocal/international guideline to treat CKD risk factors.

In one aspect, the patient is a non-diabetic patient. In one aspect, thepatient is a patient with pre-diabetes or a patient with type 2 or type1 diabetes mellitus.

In one aspect, the patient is a non-diabetic and non-pre-diabeticpatient. In one aspect, the patient is not at risk or even high risk forcardiovascular events. In one aspect, the patient is a not a patientwith chronic heart failure, in particular not a patient with HFrEF(Heart Failure with reduced Ejection Fraction) and/or HFpEF (HeartFailure with preserved Ejection Fraction).

In one aspect, empagliflozin is administered at a dose in a range from0.5 mg to 25 mg, for example from 1 mg to 25 mg, for example at a doseof 10 mg or 25 mg. In one aspect, empagliflozin is administered oncedaily to the patient.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin optionally incombination with one or more other therapeutic substances for use as amedicament in any one of the methods described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin optionally incombination with one or more other therapeutic substances for use in amethod for treatment, prevention, slowing the progression or riskreduction in any one of the diseases or conditions described herein.

The present invention further provides for empagliflozin or apharmaceutical composition comprising empagliflozin optionally incombination with one or more other therapeutic substances for use in themanufacture of a medicament for use in any one of the methods describedherein.

In the methods according to the present invention empagliflozin isoptionally administered in combination with one or more othertherapeutic substances to the patient.

Further aspects of the present invention become apparent to the oneskilled in the art by the description hereinbefore and in the followingand by the examples.

Definitions

The term “active ingredient” of a pharmaceutical composition accordingto the present invention means the SGLT2 inhibitor empagliflozinaccording to the present invention. An “active ingredient” is alsosometimes referred to herein as an “active substance”.

The term “body mass index” or “BMI” of a human patient is defined as theweight in kilograms divided by the square of the height in meters, suchthat BMI has units of kg/m².

The term “overweight” is defined as the condition wherein the individualhas a BMI greater than or 25 kg/m² and less than 30 kg/m². The terms“overweight” and “pre-obese” are used interchangeably.

The terms “obesity” or “being obese” and the like are defined as thecondition wherein the individual has a BMI equal to or greater than 30kg/m². According to a WHO definition the term obesity may be categorizedas follows: the term “class I obesity” is the condition wherein the BMIis equal to or greater than 30 kg/m² but lower than 35 kg/m²; the term“class II obesity” is the condition wherein the BMI is equal to orgreater than 35 kg/m² but lower than 40 kg/m²; the term “class Illobesity” is the condition wherein the BMI is equal to or greater than 40kg/m².

The indication obesity includes in particular exogenic obesity,hyperinsulinaemic obesity, hyperplasmic obesity, hyperphyseal adiposity,hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity,symptomatic obesity, infantile obesity, upper body obesity, alimentaryobesity, hypogonadal obesity, central obesity, visceral obesity,abdominal obesity.

The term “visceral obesity” is defined as the condition wherein awaist-to-hip ratio of greater than or equal to 1.0 in men and 0.8 inwomen is measured. It defines the risk for insulin resistance and thedevelopment of pre-diabetes.

The term “abdominal obesity” is usually defined as the condition whereinthe waist circumference is >40 inches or 102 cm in men, and is >35inches or 94 cm in women. With regard to a Japanese ethnicity orJapanese patients abdominal obesity may be defined as waistcircumference 85 cm in men and 90 cm in women (see e.g. investigatingcommittee for the diagnosis of metabolic syndrome in Japan).

The term “euglycemia” is defined as the condition in which a subject hasa fasting blood glucose concentration within the normal range, greaterthan 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L). Theword “fasting” has the usual meaning as a medical term.

The term “hyperglycemia” is defined as the condition in which a subjecthas a fasting blood glucose concentration above the normal range,greater than 100 mg/dL (5.6 mmol/L). The word “fasting” has the usualmeaning as a medical term.

The term “hypoglycemia” is defined as the condition in which a subjecthas a blood glucose concentration below the normal range, in particularbelow 70 mg/dL (3.89 mmol/L).

The term “postprandial hyperglycemia” is defined as the condition inwhich a subject has a 2 hour postprandial blood glucose or serum glucoseconcentration greater than 200 mg/dL (11.11 mmol/L).

The term “impaired fasting blood glucose” or “IFG” is defined as thecondition in which a subject has a fasting blood glucose concentrationor fasting serum glucose concentration in a range from 100 to 125 mg/dl(i.e. from 5.6 to 6.9 mmol/1), in particular greater than 110 mg/dL andless than 126 mg/dl (7.00 mmol/L). A subject with “normal fastingglucose” has a fasting glucose concentration smaller than 100 mg/dl,i.e. smaller than 5.6 mmol/l.

The term “impaired glucose tolerance” or “IGT” is defined as thecondition in which a subject has a 2 hour postprandial blood glucose orserum glucose concentration greater than 140 mg/dl (7.78 mmol/L) andless than 200 mg/dL (11.11 mmol/L). The abnormal glucose tolerance, i.e.the 2 hour postprandial blood glucose or serum glucose concentration canbe measured as the blood sugar level in mg of glucose per dL of plasma 2hours after taking 75 g of glucose after a fast. A subject with “normalglucose tolerance” has a 2 hour postprandial blood glucose or serumglucose concentration smaller than 140 mg/dl (7.78 mmol/L).

The term “hyperinsulinemia” is defined as the condition in which asubject with insulin resistance, with or without euglycemia, has fastingor postprandial serum or plasma insulin concentration elevated abovethat of normal, lean individuals without insulin resistance, having awaist-to-hip ratio <1.0 (for men) or <0.8 (for women).

The terms “insulin-sensitizing”, “insulin resistance-improving” or“insulin resistance-lowering” are synonymous and used interchangeably.

The term “insulin resistance” is defined as a state in which circulatinginsulin levels in excess of the normal response to a glucose load arerequired to maintain the euglycemic state (Ford E S, et al. JAMA. (2002)287:356-9). A method of determining insulin resistance is theeuglycaemic-hyperinsulinaemic clamp test. The ratio of insulin toglucose is determined within the scope of a combined insulin-glucoseinfusion technique. There is found to be insulin resistance if theglucose absorption is below the 25th percentile of the backgroundpopulation investigated (WHO definition). Rather less laborious than theclamp test are so called minimal models in which, during an intravenousglucose tolerance test, the insulin and glucose concentrations in theblood are measured at fixed time intervals and from these the insulinresistance is calculated. With this method, it is not possible todistinguish between hepatic and peripheral insulin resistance.

Furthermore, insulin resistance, the response of a patient with insulinresistance to therapy, insulin sensitivity and hyperinsulinemia may bequantified by assessing the “homeostasis model assessment to insulinresistance (HOMA-IR)” score, a reliable indicator of insulin resistance(Katsuki A, et al. Diabetes Care 2001; 24: 362-5). Further reference ismade to methods for the determination of the HOMA-index for insulinsensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), of theratio of intact proinsulin to insulin (Forst et al., Diabetes 2003,52(Suppl.1): A459) and to an euglycemic clamp study. In addition, plasmaadiponectin levels can be monitored as a potential surrogate of insulinsensitivity. The estimate of insulin resistance by the homeostasisassessment model (HOMA)-IR score is calculated with the formula (GalvinP, et al. Diabet Med 1992; 9:921-8):

HOMA-IR=[fasting serum insulin (μU/mL)]×[fasting plasmaglucose(mmol/L)/22.5]

Insulin resistance can be confirmed in these individuals by calculatingthe HOMA-IR score. For the purpose of this invention, insulin resistanceis defined as the clinical condition in which an individual has aHOMA-IR score >4.0 or a HOMA-IR score above the upper limit of normal asdefined for the laboratory performing the glucose and insulin assays.

As a rule, other parameters are used in everyday clinical practice toassess insulin resistance. Preferably, the patient's triglycerideconcentration is used, for example, as increased triglyceride levelscorrelate significantly with the presence of insulin resistance.

Individuals likely to have insulin resistance are those who have two ormore of the following attributes: 1) overweight or obese, 2) high bloodpressure, 3) hyperlipidemia, 4) one or more 1^(st) degree relative witha diagnosis of IGT or IFG or type 2 diabetes.

Patients with a predisposition for the development of IGT or IFG or type2 diabetes are those having euglycemia with hyperinsulinemia and are bydefinition, insulin resistant. A typical patient with insulin resistanceis usually overweight or obese. If insulin resistance can be detected,this is a particularly strong indication of the presence ofpre-diabetes. Thus, it may be that in order to maintain glucosehomoeostasis a person needs 2-3 times as much insulin as a healthyperson, without this resulting in any clinical symptoms.

“Pre-diabetes” is a general term that refers to an intermediate stagebetween normal glucose tolerance (NGT) and overt type 2 diabetesmellitus (T2DM), also referred to as intermediate hyperglycaemia.Therefore in one aspect of the present invention “pre-diabetes” isdiagnosed in an individual if HbA1c is more or equal to 5.7% and lessthan 6.5%. According to another aspect of this invention “pre-diabetes”represents 3 groups of individuals, those with impaired glucosetolerance (IGT) alone, those with impaired fasting glucose (IFG) aloneor those with both IGT and IFG. IGT and IFG usually have distinctpathophysiologic etiologies, however also a mixed condition withfeatures of both can exist in patients. Therefore in another aspect ofthe present invention a patient being diagnosed of having “pre-diabetes”is an individual with diagnosed IGT or diagnosed IFG or diagnosed withboth IGT and IFG. Following the definition according to the AmericanDiabetes Association (ADA) and in the context an aspect of the presentinvention a patient being diagnosed of having “pre-diabetes” is anindividual with:

a) a fasting plasma glucose (FPG) concentration <100 mg/dL [1mg/dL=0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration,measured by a 75-g oral glucose tolerance test (OGTT), ranging between≥140 mg/dL and <200 mg/dL (i.e., IGT); or

b) a fasting plasma glucose (FPG) concentration between ≥100 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT) of <140 mg/dL (i.e., IFG); or

c) a fasting plasma glucose (FPG) concentration between ≥100 mg/dL and<126 mg/dL and a 2-hour plasma glucose (PG) concentration, measured by a75-g oral glucose tolerance test (OGTT), ranging between ≥140 mg/dL and<200 mg/dL (i.e., both IGT and IFG).

Patients with “pre-diabetes” are individuals being pre-disposed to thedevelopment of type 2 diabetes. Pre-diabetes extends the definition ofIGT to include individuals with a fasting blood glucose within the highnormal range 100 mg/dL (J. B. Meigs, et al. Diabetes 2003;52:1475-1484). The scientific and medical basis for identifyingpre-diabetes as a serious health threat is laid out in a PositionStatement entitled “The Prevention or Delay of Type 2 Diabetes” issuedjointly by the American Diabetes Association and the National Instituteof Diabetes and Digestive and Kidney Diseases (Diabetes Care 2002;25:742-749).

The methods to investigate the function of pancreatic beta-cells aresimilar to the above methods with regard to insulin sensitivity,hyperinsulinemia or insulin resistance: An improvement of beta-cellfunction can be measured for example by determining a HOMA-index(homeostasis model assessment) for beta-cell function, HOMA-B, (Matthewset al., Diabetologia 1985, 28: 412-19), the ratio of intact proinsulinto insulin (Forst et al., Diabetes 2003, 52(Suppl.1): A459), first andsecond phase insulin secretion after an oral glucose tolerance test or ameal tolerance test (Stumvoll et al., Diabetes care 2000, 23: 295-301),the insulin/C-peptide secretion after an oral glucose tolerance test ora meal tolerance test, or by employing a hyperglycemic clamp studyand/or minimal modeling after a frequently sampled intravenous glucosetolerance test (Stumvoll et al., Eur J Clin Invest 2001, 31: 380-81).

The term “type 1 diabetes” is defined as the condition in which asubject has, in the presence of autoimmunity towards the pancreaticbeta-cell or insulin, a fasting blood glucose or serum glucoseconcentration greater than 125 mg/dL (6.94 mmol/L). If a glucosetolerance test is carried out, the blood sugar level of a diabetic willbe in excess of 200 mg of glucose per dL (11.1 mmol/1) of plasma 2 hoursafter 75 g of glucose have been taken on an empty stomach, in thepresence of autoimmunity towards the pancreatic beta cell or insulin. Ina glucose tolerance test 75 g of glucose are administered orally to thepatient being tested after 10-12 hours of fasting and the blood sugarlevel is recorded immediately before taking the glucose and 1 and 2hours after taking it. The presence of autoimmunity towards thepancreatic beta-cell may be observed by detection of circulating isletcell autoantibodies [“type 1A diabetes mellitus” ], i.e., at least oneof: GAD65 [glutamic acid decarboxylase-65], ICA [islet-cell cytoplasm],IA-2 [intracytoplasmatic domain of the tyrosine phosphatase-like proteinIA-2], ZnT8 [zinc-transporter-8] or anti-insulin; or other signs ofautoimmunity without the presence of typical circulating autoantibodies[type 1B diabetes], i.e. as detected through pancreatic biopsy orimaging). Typically a genetic predisposition is present (e.g. HLA, INSVNTR and PTPN22), but this is not always the case.

The term “type 2 diabetes mellitus” or “T2DM” is defined as thecondition in which a subject has a fasting blood glucose or serumglucose concentration greater than 125 mg/dL (6.94 mmol/L). Themeasurement of blood glucose values is a standard procedure in routinemedical analysis. If a glucose tolerance test is carried out, the bloodsugar level of a diabetic will be in excess of 200 mg of glucose per dL(11.1 mmol/1) of plasma 2 hours after 75 g of glucose have been taken onan empty stomach. In a glucose tolerance test 75 g of glucose areadministered orally to the patient being tested after 10-12 hours offasting and the blood sugar level is recorded immediately before takingthe glucose and 1 and 2 hours after taking it. In a healthy subject, theblood sugar level before taking the glucose will be between 60 and 110mg per dL of plasma, less than 200 mg per dL 1 hour after taking theglucose and less than 140 mg per dL after 2 hours. If after 2 hours thevalue is between 140 and 200 mg, this is regarded as abnormal glucosetolerance.

The term “late stage type 2 diabetes mellitus” includes patients with asecondary drug failure, indication for insulin therapy and progressionto micro- and macrovascular complications e.g. diabetic nephropathy, orcoronary heart disease (CHD).

The term “LADA” (“latent autoimmune diabetes of adults”) refers topatients that have a clinical diagnosis of type 2 diabetes, but who arebeing detected to have autoimmunity towards the pancreatic beta cell.Latent autoimmune diabetes of adults (LADA) is also known as slowlyprogressive type 1 diabetes mellitus (T1DM), “mild” T1DM, non-insulindependent type 1 DM, type 1½ DM, double diabetes or antibody positivetype 2 DM (T2DM). LADA is often not clearly defined and, opposed toT1DM, seldom or never presents with significant weight loss andketoacidosis due to rapidly progressive β-cell failure.

The term “HbA1c” refers to the product of a non-enzymatic glycation ofthe haemoglobin B chain. Its determination is well known to one skilledin the art. In monitoring the treatment of diabetes mellitus the HbA1cvalue is of exceptional importance. As its production dependsessentially on the blood sugar level and the life of the erythrocytes,the HbA1c in the sense of a “blood sugar memory” reflects the averageblood sugar levels of the preceding 4-6 weeks. Diabetic patients whoseHbA1c value is consistently well adjusted by intensive diabetestreatment (i.e. <6.5% of the total haemoglobin in the sample), aresignificantly better protected against diabetic microangiopathy. Forexample, metformin on its own achieves an average improvement in theHbA1c value in the diabetic of the order of 1.0-1.5%. This reduction ofthe HbA1C value is not sufficient in all diabetics to achieve thedesired target range of <7% or <6.5% and preferably <6% HbA1c.

The term “insufficient glycemic control” or “inadequate glycemiccontrol” in the scope of the present invention means a condition whereinpatients show HbA1c values above 6.5%, in particular above 7.0%, evenmore preferably above 7.5%, especially above 8%.

The “metabolic syndrome”, also called “syndrome X” (when used in thecontext of a metabolic disorder), also called the “dysmetabolicsyndrome” is a syndrome complex with the cardinal feature being insulinresistance (Laaksonen D E, et al. Am J Epidemiol 2002; 156:1070-7).According to the ATP III/NCEP guidelines (Executive Summary of the ThirdReport of the National Cholesterol Education Program (NCEP) Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III) JAMA: Journal of the American MedicalAssociation (2001) 285:2486-2497), diagnosis of the metabolic syndromeis made when three or more of the following risk factors are present:

-   -   1. Abdominal obesity, defined as waist circumference >40 inches        or 102 cm in men, and >35 inches or 94 cm in women; or with        regard to a Japanese ethnicity or Japanese patients defined as        waist circumference 85 cm in men and 90 cm in women;    -   2. Triglycerides: ≥150 mg/dL    -   3. HDL-cholesterol <40 mg/dL in men    -   4. Blood pressure ≥130/85 mm Hg (SBP≥130 or DBP≥85)    -   5. Fasting blood glucose ≥100 mg/dL

The NCEP definitions have been validated (Laaksonen D E, et al. Am JEpidemiol. (2002) 156:1070-7). Triglycerides and HDL cholesterol in theblood can also be determined by standard methods in medical analysis andare described for example in Thomas L (Editor): “Labor und Diagnose”,TH-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000.

According to a commonly used definition, hypertension is diagnosed ifthe systolic blood pressure (SBP) exceeds a value of 140 mm Hg anddiastolic blood pressure (DBP) exceeds a value of 90 mm Hg. If a patientis suffering from manifest diabetes it is currently recommended that thesystolic blood pressure be reduced to a level below 130 mm Hg and thediastolic blood pressure be lowered to below 80 mm Hg.

The term “empagliflozin” refers to the SGLT2 inhibitor1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzeneof the formula

as described for example in WO 2005/092877. Methods of synthesis aredescribed in the literature, for example WO 06/120208 and WO2011/039108. According to this invention, it is to be understood thatthe definition of empagliflozin also comprises its hydrates, solvatesand polymorphic forms thereof, and prodrugs thereof. An advantageouscrystalline form of empagliflozin is described in WO 2006/117359 and WO2011/039107 which hereby are incorporated herein in their entirety. Thiscrystalline form possesses good solubility properties which enables agood bioavailability of the SGLT2 inhibitor. Furthermore, thecrystalline form is physico-chemically stable and thus provides a goodshelf-life stability of the pharmaceutical composition. Preferredpharmaceutical compositions, such as solid formulations for oraladministration, for example tablets, are described in WO 2010/092126,which hereby is incorporated herein in its entirety.

The terms “treatment” and “treating” comprise therapeutic treatment ofpatients having already developed said condition, in particular inmanifest form. Therapeutic treatment may be symptomatic treatment inorder to relieve the symptoms of the specific indication or causaltreatment in order to reverse or partially reverse the conditions of theindication or to stop or slow down progression of the disease. Thus thecompositions and methods of the present invention may be used forinstance as therapeutic treatment over a period of time as well as forchronic therapy.

The terms “prophylactically treating”, “preventivally treating” and“preventing” are used interchangeably and comprise a treatment ofpatients at risk to develop a condition mentioned hereinbefore, thusreducing said risk.

The term “tablet” comprises tablets without a coating and tablets withone or more coatings. Furthermore the “term” tablet comprises tabletshaving one, two, three or even more layers and press-coated tablets,wherein each of the beforementioned types of tablets may be without orwith one or more coatings. The term “tablet” also comprises mini, melt,chewable, effervescent and orally disintegrating tablets.

The terms “pharmacopoe” and “pharmacopoeias” refer to standardpharmacopoeias such as the “USP 31-NF 26 through Second Supplement”(United States Pharmacopeial Convention) or the “European Pharmacopoeia6.3” (European Directorate for the Quality of Medicines and Health Care,2000-2009).

The term “chronic kidney disease (CDK)” is defined as abnormalities ofkidney structure or function, present for more than three months, withimplications for health. CKD is classified based on cause, GFR category,and albuminuria category (CGA).

CKD has been classified into 5 stages, where stage 1 is kidney damagewith normal GFR (mL/min/1.73 m2) of 90 or above; stage 2 is kidneydamage with a mild decrease in GFR (GFR 60-89); stage 3 is a moderatedecrease in GFR (GFR 30-59); stage 4 is a severe decrease in GFR (GFR15-29); and stage 5 is kidney failure (GFR<15 or dialysis). Stage 3 hasbeen subdivided into stage 3A, which is a mild to moderate decrease inGFR (GFR 45-59), and stage 3B, which is a moderate to severe decrease inGFR (GFR 30-44).

The term “albuminuria” is defined as a condition wherein more than thenormal amount of albumin is present in the urine. Albuminuria can bedetermined by the albumin excretion rate (AER) and/or thealbumin-to-creatine ratio (ACR) in the urine (also referred to as UACR).Albuminuria categories in CKD are defined as follows:

ACR Cate- AER (approximate equivalent) gory (mg/24 hours) (mg/mmol)(mg/g) Terms A1 <30 <3 <30 Normal to mildly increased A2 30-300 3-3030-300 Moderately increased A3 >300 >30 >300 Severely increased

Category A1 reflects no albuminuria, category A2 reflectsmicroalbuminuria, category A3 reflects macroalbuminuria. The progressionof category A1 usually leads to microalbuminuria (A2) but may alsodirectly result in macroalbuminuria (A3). Progression ofmicroalbuminuria (A2) results in macroalbuminuria (A3).

The term “eGFR” refers to the estimated glomerular filtration rate(GFR). The GFR describes the flow rate of filtered fluid through thekidney. The estimated GFR may be calculated based on serum creatininevalues e.g. using the Chronic Kidney Disease Epidemiology Collaboration(CKD-EPI) equation (also abbreviated as (CKD-EPI)cr), theCockcroft-Gault formula or the Modification of Diet in Renal Disease(MDRD) formula, which are all known in the art.

According to an aspect of this invention the estimated glomerularfiltration rate (eGFR) is derived from serum creatinine values, age sexand race based on the CKD-EPI equation:

GFR=141×min(S _(cr)/κ,1)^(α)×max(S _(cr)/K,1)^(−1.209)×0.993^(Age)×1.018[if female]×1.159 [if black]

where:

Scr is serum creatinine in mg/dL,

κ IS 0.7 for females and 0.9 for males,

α is −0.329 for females and −0.411 for males,

min indicates the minimum of S_(cr)/κ or 1, and

max indicates the maximum of S_(cr)/κ or 1.

For the purpose of the present invention, the degree of renal impairmentin a patient is defined by the following estimated glomerular filtrationrate (eGFR):

Normal renal function (CKD stage 1): eGFR≥90 mL/min/1.73 m²

Mild renal impairment (CKD stage 2): eGFR≥60 to <90 mL/min/1.73 m²

Moderate renal impairment (CKD stage 3): eGFR≥30 to <60 mL/min/1.73 m²

Severe renal impairment (CKD stage 4): eGFR≥15 to <30 mL/min/1.73 m²

Kidney failure (CKD stage 5): eGFR<15 mL/min/1.73 m²

According to the present invention moderate renal impairment can befurther divided into two sub-stages:

Moderate A renal impairment (CKD 3A): eGFR≥45 to <60 mL/min/1.73 m²

Moderate B renal impairment (CKD 3B): eGFR≥30 to <45 mL/min/1.73 m²

DETAILED DESCRIPTION OF THE INVENTION

Beyond an improvement of glycemic control and weight loss due to anincrease in urinary glucose excretion, empagliflozin shows a diureticeffect, reduced arterial stiffness and direct vascular effects (Cherneyet al., Cardiovasc Diabetol. 2014; 13:28; Cherney et al., Circulation.2014; 129:587-597). In the EMPA-REG OUTCOME™ study it was demonstratedthat empagliflozin reduced the risk of cardiovascular death,hospitalization for heart failure and overall mortality in patients withtype 2 diabetes mellitus and high cardiovascular risk (Zinman et al., NEngl J Med. 2015; 373:2117-2128). It was observed that treatment withempagliflozin leads to blood pressure reductions without clinicallyrelevant changes of the heart rate, thus improving rate pressure product(RPP), a surrogate marker of cardiac oxygen demand. Furthermoreempagliflozin was found of not being associated with clinically relevantreflex-mediated sympathetic activation in contrast to increases observedwith diuretics. It may be assumed that altered glucose and sodiumgradients within the kidney may generate a sympathoinhibitory afferentrenal nerve signal. The lack of sympathetic activation may contribute toa beneficial cardiovascular and renal profile of empagliflozin(cardiorenal axis). Based on clinical and non-clinical studies includingmechanistic considerations, such as the effect of empagliflozin on humanautonomic cardiovascular regulation, the use of empagliflozin in thetreatment, prevention or slowing the progression of certain diseases andconditions or reducing the risk thereof, in particular chronic kidneydisease and cardiovascular death in certain patients, is describedhereinbefore and hereinafter.

According to one embodiment, this invention provides a method oftreating, reducing the risk of or slowing the progression of chronickidney disease in a patient with chronic kidney disease, said methodcomprising administering empagliflozin to the patient.

According to one embodiment, this invention provides a method fortreating, preventing, protecting against, reducing the risk of, delayingthe occurrence of and/or delaying the progression of chronic kidneydisease in a patient not diagnosed with chronic heart failure comprisingadministering empagliflozin to the patient wherein the patient is anon-diabetic patient. In particular this embodiment relates to a methodfor treating and/or delaying the progression of chronic kidney diseasein the patient. According to an aspect of this embodiment the patient isa patient with stage 3, including stage 3a and/or 3b, chronic kidneydisease. According to another aspect of this embodiment the patient is apatient with stage 4 chronic kidney disease.

Chronic kidney disease (CKD), also known as chronic renal disease, is aprogressive loss in renal function over a period of months or years.Patients with renal disease, renal dysfunction or renal impairment mayinclude patients with chronic renal insufficiency or impairment, whichcan be stratified (if not otherwise noted) according to glomerularfiltration rate (GFR, ml/min/1.73 m²) into 5 disease stages: stage 1characterized by normal GFR≥90 plus either persistent albuminuria (e.g.UACR≥30 mg/g) or known structural or hereditary renal disease; stage 2characterized by mild reduction of GFR (GFR 60-89) describing mild renalimpairment; stage 3 characterized by moderate reduction of GFR (GFR30-59) describing moderate renal impairment; stage 4 characterized bysevere reduction of GFR (GFR 15-29) describing severe renal impairment;and terminal stage 5 characterized by requiring dialysis or GFR<15describing established kidney failure (end-stage renal disease, ESRD).

Chronic kidney disease and its stages (CKD 1-5) can be usuallycharacterized or classified accordingly, such as based on the presenceof either kidney damage (albuminuria) or impaired estimated glomerularfiltration rate (GFR<60 [ml/min/1.73 m²], with or without kidneydamage).

Generally, mild renal impairment according to the present inventioncorresponds to stage 2 chronic kidney disease, moderate renal impairmentaccording to the present invention generally corresponds to stage 3chronic kidney disease, and severe renal impairment according to thepresent invention generally corresponds to stage 4 chronic kidneydisease. Likewise, moderate A renal impairment according to the presentinvention generally corresponds to stage 3A chronic kidney disease andmoderate B renal impairment according to the present invention generallycorresponds to stage 3B chronic kidney disease.

According to an embodiment, this invention provides a method forreducing the risk of cardiovascular death in a patient with chronickidney disease.

According to an embodiment, this invention provides a method forreducing the risk of all-cause mortality in a patient with chronickidney disease.

According to an embodiment, this invention provides a method forreducing the risk of hospitalization in a patient with chronic kidneydisease.

According to an embodiment, this invention provides a method forreducing the risk of heart failure hospitalization in a patient withchronic kidney disease.

According to an embodiment, this invention provides a method forreducing the risk of all cause hospitalization in a patient with chronickidney disease.

According to an embodiment this invention provides a method for reducingthe risk of any of cardiovascular death (including fatal stroke, fatalmyocardial infarction and sudden death), non-fatal myocardial infarction(excluding silent myocardial infarction), non-fatal stroke (theso-called 3-point MACE) in a patient with chronic kidney disease.

In another embodiment, the present invention provides a method ofpreventing, reducing the risk of or delaying the occurrence of acardiovascular event, said method comprising administeringempagliflozin, optionally in combination with one or more othertherapeutic substances, to the CKD patient. In one embodiment, thecardiovascular event is selected from cardiovascular death, non-fatalmyocardial infarction, non-fatal stroke, hospitalisation for unstableangina pectoris and heart failure requiring hospitalisation. In oneembodiment, the cardiovascular death is due to fatal myocardialinfarction or fatal stroke. In one embodiment, the cardiovascular deathis due to sudden death or heart failure death.

In one embodiment, the present invention provides a method of treating,reducing the risk of or slowing the progression of chronic kidneydisease and reducing the risk of cardiovascular death in a patient withchronic kidney disease, the method comprising administeringempagliflozin to the patient. In one aspect the patient has moderatelyor severely decreased renal function or elevated albuminuria levels, forexample ≥200 mg/g.

In one aspect, the patient has an eGFR≥20 to <45 mL/min/1.73 m². In oneaspect, the patient has an eGFR≥20 mL/min/1.73 m² and a urinaryalbumin-to-creatine ratio (UACR)≥200 mg/g. In one aspect, the patienthas an eGFR≥45 and <90 ml/min/1.73 m² and a urinary albumin-to-creatineratio (UACR)≥200 mg/g.

In one aspect, the patient is treated with a RAAS inhibitor(Renin-Angiotensin-Aldosterone System). In one aspect, the patient istreated with an Angiotensin-Converting Enzyme (ACE) inhibitor and/or anangiotensin II receptor blocker (ARB). In one aspect, the patient is onstandard of care according to local/international guideline to treat CKDrisk factors.

In one aspect, the patient is a non-diabetic patient. In one aspect, thepatient is a patient with pre-diabetes or a patient with type 2 or type1 diabetes mellitus.

In one aspect, the patient is a non-diabetic and non-pre-diabeticpatient. In one aspect, the patient is not at risk or even high risk forcardiovascular events. In one aspect, the patient is a not a patientwith chronic heart failure, in particular not a patient with HFrEF(Heart Failure with reduced Ejection Fraction) and/or HFpEF (HeartFailure with preserved Ejection Fraction).

In one aspect, empagliflozin is administered at a dose in a range from 1mg to 25 mg, for example at a dose of 10 mg or 25 mg. In one aspect,empagliflozin is administered once daily to the patient.

In one aspect, empagliflozin slows or delays the time to the firstoccurrence of any of the following components:

-   -   CV death    -   sustained decrease of 40% or more in eGFR, e.g. via (CKD-EPI)cr    -   incidence of ESRD defined by either        -   continuous renal replacement therapy (dialysis or renal            transplantation) or        -   sustained eGFR<15 ml/min/1.73 m² for patients with baseline            eGFR≥30 ml/min/1.73 m² or eGFR<10 ml/min/1.73 m² for            patients with baseline eGFR<30 ml/min/1.73 m²

In one aspect, empagliflozin slows or delays the time to the firstoccurrence of renal disease progression as defined by one or more of thefollowing:

-   -   sustained decrease of 40% or more in eGFR, e.g. via (CKD-EPI)cr    -   sustained eGFR<10 ml/min/1.73 m²    -   Incidence of ESRD defined by continuous renal replacement        therapy (by either dialysis or renal transplantation) or    -   renal death

In one aspect, empagliflozin slows or delays the time to the firstoccurrence of any of the following components: Occurrence of

-   -   All-cause mortality or all-cause hospitalization    -   All-cause hospitalization    -   All-cause mortality    -   eGFR (e.g. via (CKD-EPI)cr) slope of change from baseline    -   Cardiovascular death or hospitalization for heart failure

In one aspect, empagliflozin slows or delays the time to any one of thefollowing components:

-   -   Time to CV death confirmed by adjudication    -   Time to first occurrence of sustained decrease of 40% or more in        eGFR confirmed by adjudication    -   Time to first incidence of ESRD confirmed by adjudication    -   Time to first hospitalization for congestive heart failure        confirmed by adjudication    -   Time to first all-cause hospitalization    -   Time to all-cause mortality    -   Time to first 3-MACE (i.e. CV death, non-fatal MI, non-fatal        stroke) confirmed by adjudication    -   Time to first occurrence of all-cause mortality, sustained        decrease of 40% or more in eGFR or incidence of ESRD confirmed        by adjudication    -   Time to first occurrence of all-cause mortality, sustained        decrease of 50% or more in eGFR or incidence of ESRD confirmed        by adjudication    -   Time to first occurrence of all-cause mortality, sustained        decrease of 57% or more in eGFR or incidence of ESRD confirmed        by adjudication    -   Time to first occurrence of composite renal endpoint (sustained        decrease of 40% or more in eGFR, incidence of ESRD) confirmed by        adjudication    -   Time to first occurrence of composite renal endpoint 2        (sustained decrease of 50% or more in eGFR, incidence of ESRD)        confirmed by adjudication    -   Time to first occurrence of composite renal endpoint 3        (sustained decrease of 57% or more in eGFR, incidence of ESRD)        confirmed by adjudication    -   Time to first sustained decrease of 57% or more in eGFR        confirmed by adjudication    -   Time to first sustained decrease of 50% or more in eGFR        confirmed by adjudication    -   Time to first sustained decrease of 30% or more in eGFR        confirmed by adjudication    -   Time to first incidence of acute renal failure (incl. AKI)        confirmed by adjudication    -   Time to first incidence of AKI confirmed by adjudication    -   Time to onset of DM (defined as HbA1c≥6.5% or as diagnosed by        the Investigator) in patients without DM defined as no history        of DM and HbA1c<6.5% at baseline

In the methods according to the present invention empagliflozin isoptionally administered in combination with one or more othertherapeutic substances to the patient.

According to an embodiment of the methods as described hereinbefore andhereinafter the patient is a non-diabetic patient, a patient withpre-diabetes, a patient with type 2 diabetes mellitus or a patient withtype 1 diabetes mellitus.

According to another embodiment of the methods as described hereinbeforeand hereinafter the patient is a patient with pre-diabetes. According toan aspect of this embodiment the patient has a HbA1c more or equal to5.7% and less than 6.5%.

According to another embodiment of the methods as described hereinbeforeand hereinafter the patient is a patient with pre-diabetes or anon-diabetic patient. According to an aspect of this embodiment thepatient has a HbA1c less than 6.5%.

According to another embodiment of the methods as described hereinbeforeand hereinafter the patient is a non-diabetic patient, in particular anon-diabetic and non-pre-diabetic patient. According to an aspect ofthis embodiment the patient has a HbA1c less than 5.7%.

According to another aspect the non-diabetic patient does not show animpaired glucose tolerance (IGT), i.e. the patient shows a normalglucose tolerance. For example the 2 hour postprandial blood glucose orplasma glucose (PG) concentration is smaller than 140 mg/dl (7.78mmol/L).

According to another aspect the non-diabetic patient does not show animpaired fasting blood glucose (IFG), i.e. the patient shows a normalfasting glucose. For example the fasting plasma glucose concentration(FPG) is smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/1.

In particular the non-diabetic patient does not show an impaired fastingblood glucose (IFG) and does not show an impaired glucose tolerance(IGT), i.e. the patient shows a normal glucose tolerance and a normalglucose tolerance. For example the fasting plasma glucose concentration(FPG) is smaller than 100 mg/dl, i.e. smaller than 5.6 mmol/1, and the 2hour postprandial blood glucose or plasma glucose (PG) concentration issmaller than 140 mg/dl (7.78 mmol/L).

According to an embodiment of the methods as described hereinbefore andhereinafter empagliflozin is administered at a dose in a range from 0.5to 25 mg per day, for example 1 to 25 mg per day, for example at a doseof 1 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg or 25 mg per day to the patient.The administration of empagliflozin may occur one or two times a day,most preferably once a day. For example a dose for once dailyadministration is 10 mg or 25 mg. The preferred route of administrationis oral administration.

According to a particular aspect of the present invention empagliflozinis administered at a dose of 10 mg per day to the patient.

According to another particular aspect of the present inventionempagliflozin is administered at a dose of 25 mg per day to the patient.

Preferably empagliflozin is administered orally to the patient oncedaily.

In one embodiment, patients within the meaning of this invention mayinclude patients with chronic heart failure who have not previously beentreated with a drug to treat chronic heart failure(heart-failure-drug-naïve patients). Thus, in an embodiment, thetherapies described herein may be used in heart-failure-drug-naïvepatients.

In another embodiment, patients within the meaning of this invention mayinclude patients with chronic heart failure and with pre-diabetes orwith type 2 diabetes mellitus (T2DM) who have not previously beentreated with an antidiabetic drug (T2DM-drug-naïve patients). Thus, inan embodiment, the therapies described herein may be used inT2DM-drug-naïve patients.

Furthermore, the methods according to this invention are particularlysuitable in the treatment of patients with chronic heart failure andwith insulin dependency, i.e. in patients who are treated or otherwisewould be treated or need treatment with an insulin or a derivative ofinsulin or a substitute of insulin or a formulation comprising aninsulin or a derivative or substitute thereof. These patients includepatients with diabetes type 2 and patients with diabetes type 1.

Furthermore, it can be found that the administration of a pharmaceuticalcomposition according to this invention results in no risk or in a lowrisk of hypoglycemia. Therefore, a treatment or prophylaxis according tothis invention is also advantageously possible in those patients showingor having an increased risk for hypoglycemia.

By the administration of empagliflozin excessive blood glucose isexcreted through the urine of the patient based on the SGLT2 inhibitingactivity, so that no gain in weight or even a reduction in body weightof the patient may result. Therefore, the methods according to thisinvention are advantageously suitable in those patients with chronicheart failure who are diagnosed of one or more of the conditionsselected from the group consisting of overweight and obesity, inparticular class I obesity, class II obesity, class Ill obesity,visceral obesity and abdominal obesity. In addition a method accordingto this invention is advantageously suitable in those patients in whicha weight increase is contraindicated.

When this invention refers to patients requiring treatment orprevention, it relates primarily to treatment and prevention in humans,but the pharmaceutical composition may also be used accordingly inveterinary medicine in mammals. In the scope of this invention adultpatients are preferably humans of the age of 18 years or older. Also inthe scope of this invention, patients are adolescent humans, i.e. humansof age 6 to 17 years, for example 10 to 17 years, preferably of age 13to 17 years.

According to an embodiment of the present invention empagliflozin isadministered in combination with one or more other therapeuticsubstances to the patient. The combined administration may besimultaneously, separately or sequentially.

In one embodiment, the active substances that are indicated in thetreatment of chronic heart failure are selected from angiotensinreceptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors,angiotensin receptor neprilysin inhibitors (ARNi), beta-blockers,aldosterone antagonists (MRA), digoxin, ivabradine and diuretics.

In one embodiment, the antidiabetic substances are selected frommetformin, sulphonylureas, nateglinide, repaglinide, PPAR-gammaagonists, alpha-glucosidase inhibitors, insulin and insulin analogues,GLP-1 and GLP-1 analogues and DPP-4 inhibitors.

In one embodiment the patient receives standard of care medicationindicated for patients with chronic heart failure. In one aspect of thisembodiment empagliflozin is administered to the patient in combinationwith one or more active substances that are indicated in the treatmentof chronic heart failure. For example empagliflozin is adminstered incombination with one or more active substances selected from the groupconsisting of angiotensin receptor blockers (ARB),angiotensin-converting enzyme (ACE) inhibitors, beta-blockers,aldosterone antagonists, diuretics, angiotensin receptor-neprilysininhibitor (ARNi), mineralcorticoid receptor antagonists and ivabradine.According to this aspect of the embodiment the patient is for example anon-diabetic patient or a patient with pre-diabetes.

Examples of angiotensin II receptor blockers (ARBs) are telmisartan,candesartan, valsartan, losartan, irbesartan, olmesartan, azilsartan andeprosartan; the dosage(s) of some of these medications are for exampleshown below:

-   -   Candesartan (Atacand), 4 mg, 8 mg, 16 mg, or 32 mg of        candesartan cilexetil    -   Eprosartan (Teveten), 400 mg or 600 mg    -   Irbesartan (Avapro), 75 mg, 150 mg, or 300 mg of irbesartan.    -   Losartan (Cozaar), 25 mg, 50 mg or 100 mg of losartan potassium    -   Telmisartan (Micardis), 40 mg or 80 mg    -   Telmisartan (Micardis HCT), 40 mg/12.5 mg, 80 mg/12.5 mg, and 80        mg/25 mg each of telmisartan and hydrochlorothiazide    -   Telmisartan/amlodipine (Twynsta), 40 mg/5 mg, 40 mg/10 mg, 80        mg/5 mg and 80 mg/10 mg each of telmisartan and amlodipine    -   Valsartan (Diovan), 40 mg, 80 mg, 160 mg or 320 mg of valsartan

Examples of Angiotensin-Converting Enzyme (ACE) inhibitors arebenazepril, captopril, ramipril, lisinopril, Moexipril, cilazapril,quinapril, captopril, enalapril, benazepril, perindopril, fosinopril andtrandolapril; the dosage(s) of some of these medications are for exampleshown below:

-   -   Benazepril (Lotensin), 5 mg, 10 mg, 20 mg, and 40 mg for oral        administration    -   Captopril (Capoten), 12.5 mg, 25 mg, 50 mg, and 100 mg as scored        tablets for oral administration    -   Enalapril (Vasotec), 2.5 mg, 5 mg, 10 mg, and 20 mg tablets for        oral administration    -   Fosinopril (Monopril), for oral administration as 10 mg, 20 mg,        and 40 mg tablets    -   Lisinopril (Prinivil, Zestril), 5 mg, 10 mg, and 20 mg tablets        for oral administration    -   Moexipril (Univasc), 7.5 mg and 15 mg for oral administration    -   Perindopril (Aceon), 2 mg, 4 mg and 8 mg strengths for oral        administration    -   Quinapril (Accupril), 5 mg, 10 mg, 20 mg, or 40 mg of quinapril        for oral administration    -   Ramipril (Altace), 1.25 mg, 2.5 mg, 5, mg, 10 mg    -   Trandolapril (Mavik), 1 mg, 2 mg, or 4 mg of trandolapril for        oral administration

Examples of beta-blockers are acebutolol, atenolol, betaxolol,bisoprolol, celiprolol, metoprolol, nebivolol, propranolol, timolol andcarvedilol; the dosage(s) of some of these medications are for exampleshown below:

-   -   Acebutolol (Sectral), 200 or 400 mg of acebutolol as the        hydrochloride salt    -   Atenolol (Tenormin), 25, 50 and 100 mg tablets for oral        administration    -   Betaxolol (Kerlone), 10-mg and 20-mg tablets for oral        administration    -   Bisoprolol/hydrochlorothiazide (Ziac), 2.5/6 mg, 5/6.25 mg,        10/6.25 mg    -   Bisoprolol (Zebeta), 5 and 10 mg tablets for oral administration    -   Metoprolol (Lopressor, Toprol XL), 50- and 100-mg tablets for        oral administration and in 5-mL ampuls for intravenous        administration    -   Propranolol (Inderal), 10 mg, 20 mg, 40 mg, 60 mg, and 80 mg        tablets for oral administration    -   Timolol (Blocadren), 5 mg, 10 mg or 20 mg timolol maleate for        oral administration.

Examples of aldosterone antagonists are spironolactone, eplerenone,canrenone and fineronone; the dosage(s) of some of these medications arefor example shown below:

-   -   spironolactone (e.g. Aldactone), 25 or 50 mg once daily or every        second day,    -   eplerenone (e.g. Inspra), 25 or 50 mg once daily.

Examples of diuretics are bumetanide, hydrochlorothiazide, chlortalidon,chlorothiazide, hydrochlorothiazide, xipamide, indapamide, furosemide,piretanide, torasemide, spironolactone, eplerenone, amiloride andtriamterene; for example these medications are thiazide diuretics, e.g.chlorthalidone, HCT, loop diuretics, e.g. furosemide, torasemide orpotassium-sparing diuretics, e.g. eplerenone, or combination thereof;the dosage(s) of some of these medications are for example shown below:

-   -   Amiloride (Midamor), 5 mg of anhydrous amiloride HCl    -   Bumetanide (Bumex), available as scored tablets, 0.5 mg (light        green), 1 mg (yellow) and 2 mg (peach) for oral administration    -   Chlorothiazide (Diuril),    -   Chlorthalidone (Hygroton)    -   Furosemide (Lasix)    -   Hydro-chlorothiazide (Esidrix, Hydrodiuril)    -   Indapamide (Lozol) and Spironolactone (Aldactone)    -   Eplerenone (Inspra)

An example of an angiotensin receptor-neprilysin inhibitor (ARNi) is acombination of valsartan and sacubitril (Entresto).

An example of inhibition of the cardiac pacemaker I_(f) current isivabradine (Procoralan, Corlanor).

Examples of calcium channel blockers are amlodipine, nifedipine,nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine,lercanipidine, manidipine, isradipine, nilvadipine, verapamil,gallopamil and diltiazem.

Examples of medications that lower blood pressure include angiotensin IIreceptor blockers (ARBs), Angiotensin-Converting Enzyme (ACE)inhibitors, beta-blockers, diuretics and calcium channel blockers.

In another aspect of this embodiment the patient is a patient with type2 diabetes mellitus and empagliflozin is administered to the patient incombination with one or more active substances that are indicated in thetreatment of chronic heart failure and in combination with one or moreantidiabetic substances. The antidiabetic substances include metformin,sulphonylureas, nateglinide, repaglinide, PPAR-gamma agonists,alpha-glucosidase inhibitors, insulin and insulin analogues, GLP-1 andGLP-1 analogues and DPP-4 inhibitors.

Examples thereof are metformin and DPPIV inhibitors, such assitagliptin, saxaglitpin and linagliptin. The active substances that areindicated in the treatment of chronic heart failure include angiotensinreceptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors,beta-blockers, aldosterone antagonists and diuretics.

Therefore according to one aspect of the methods according to thisinvention empagliflozin is administered in combination with linagliptinto the patient. The patient according to this aspect is in particular apatient with type 2 diabetes mellitus. Preferred doses are for example10 mg empagliflozin once daily and 5 mg linagliptin once daily.

Therefore according to another aspect of the methods according to thisinvention empagliflozin is administered in combination with metforminhydrochloride to the patient. The patient according to this aspect is inparticular a patient with type 2 diabetes mellitus. Preferred doses arefor example 10 mg empagliflozin once daily or 5 mg empagliflozin twicedaily and 500 mg, 850 mg or 1000 mg metformin hydrochloride twice daily.

In one aspect of this embodiment, the number, dosage and/or regimen ofsaid medications to treat chronic heart failure is reduced in saidpatient, while the administration of empagliflozin is continued. Inanother aspect of this embodiment, the number, dosage and/or regimen ofsaid medications to treat type 2 diabetes mellitus is reduced in saidpatient, while the administration of empagliflozin is continued. In yetanother aspect of this embodiment, the numbers, dosages and/or regimensof said medications to treat type 2 diabetes mellitus and of saidmedications to treat chronic heart failure are reduced in said patient,while the administration of empagliflozin is continued.

According to an example of this aspect empagliflozin is adminstered incombination with one or more active substances selected from the groupconsisting of angiotensin receptor blockers (ARB),angiotensin-converting enzyme (ACE) inhibitors, beta-blockers,aldosterone antagonists, diuretics, angiotensin receptor-neprilysininhibitor (ARNi), mineralcorticoid receptor antagonists and ivabradinein combination with metformin or in combination with linagliptin or incombination of metformin and linagliptin.

Examples of active substances in the above described groups are known tothe one skilled in the art, including their dose strengths,administration schemes and formulations.

In the context of this invention the term metformin comprises metforminhydrochloride in the form of an immediate release, extended or slowrelease formulation. Doses of metformin hydrochloride administered tothe patient are particularly 500 mg to 2000 mg per day, for example 750mg, 1000 mg, 1500 and 2000 mg per day.

Empagliflozin and metformin may be adminstered separately in twodifferent dosage forms or combined in one dosage form. Combined dosageforms of empagliflozin and metformin as immediate release formulationsare described in WO 2011/039337 and are known for example as SYNJARDI®.Combined dosage forms of empagliflozin and metformin whereinempagliflozin is part of an immediate release formulation and metforminis part of an extended release formulation are described in WO2012/120040 and WO 2013/131967.

A preferred dose of linagliptin administered to the patient is 5 mg perday.

Empagliflozin and linagliptin may be administered separately in twodifferent dosage forms or combined in one dosage form. Combined dosageforms of empagliflozin and linagliptin are described in WO 2010/092124and are known for example as GLYXAMBI®.

Within this invention it is to be understood that the combinations,compositions or administrations in combination according to thisinvention may envisage the simultaneous, sequential or separateadministration of the active components or ingredients.

In this context, “combination” or “combined” within the meaning of thisinvention may include, without being limited, fixed and non-fixed (e.g.free) forms (including kits) and uses, such as e.g. the simultaneous,sequential or separate use of the components or ingredients.

The combined administration of this invention may take place byadministering the active components or ingredients together, such ase.g. by administering them simultaneously in one single or in twoseparate formulations or dosage forms. Alternatively, the administrationmay take place by administering the active components or ingredientssequentially, such as e.g. successively in two separate formulations ordosage forms.

For the combination therapy of this invention the active components oringredients may be administered separately (which implies that they areformulated separately) or formulated altogether (which implies that theyare formulated in the same preparation or in the same dosage form).Hence, the administration of one element of the combination of thepresent invention may be prior to, concurrent to, or subsequent to theadministration of the other element of the combination.

Unless otherwise noted, combination therapy may refer to first line,second line or third line therapy, or initial or add-on combinationtherapy or replacement therapy.

The methods according to this invention are particularly suitable in thelong term treatment or prophylaxis of the diseases and/or conditions asdescribed hereinbefore and hereinafter. The term “long term” as usedhereinbefore and hereinafter indicates a treatment of or administrationin a patient within a period of time longer than 12 weeks, preferablylonger than 25 weeks, even more preferably longer than 1 year.

The pharmaceutical composition comprising empagliflozin according to theinvention may be formulated for oral or parenteral (includingintramuscular, sub-cutaneous and intravenous) administration in liquidor solid form or in a form suitable for administration by inhalation orinsufflation. Oral administration is preferred. The pharmaceuticalcomposition may be formulated in the form of tablets, granules, finegranules, powders, capsules, caplets, soft capsules, pills, oralsolutions, syrups, dry syrups, chewable tablets, troches, effervescenttablets, drops, suspension, fast dissolving tablets, oralfast-dispersing tablets, etc. The pharmaceutical composition and thedosage forms preferably comprise one or more pharmaceutical acceptablecarriers which must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not deleterious to therecipient thereof. Examples of pharmaceutically acceptable carriers areknown to the one skilled in the art.

The pharmaceutical compositions and methods according to this inventionshow advantageous effects in the treatment and prevention of thosediseases and conditions as described hereinbefore. Advantageous effectsmay be seen for example with respect to efficacy, dosage strength,dosage frequency, pharmacodynamic properties, pharmacokineticproperties, fewer adverse effects, convenience, compliance, etc.

Methods for the manufacture of empagliflozin are known to the oneskilled in the art. Advantageously, the compounds according to thisinvention can be prepared using synthetic methods as described in theliterature, including patent applications as cited hereinbefore.Preferred methods of manufacture are described in the WO 2006/120208 andWO 2007/031548. With regard to empagliflozin an advantageous crystallineform is described in the international patent application WO 2006/117359which hereby is incorporated herein in its entirety.

Further embodiments, features and advantages of the present inventionmay become apparent from the following examples. The following examplesserve to illustrate, by way of example, the principles of the inventionwithout restricting it.

EXAMPLES Example 1A: Treatment of Patients with Chronic Kidney Disease

Empagliflozin is administered to patients in a randomised, double-blind,placebo controlled, parallel group study to compare treatment withempagliflozin 10 mg once daily with placebo as add-on therapy tostandard of care in patients with chronic kidney disease. The durationof the patients is preferably a long term treatment, for example between30 and 48 months.

Patients include individuals with presence of chronic kidney diseasewith high risk of cardiorenal events defined by at least one of thefollowing:

-   -   A) Very high levels of albuminuria (i.e. macroalbuminuria)        defined as UACR 200 mg/g creatinine and/or    -   B) Impaired renal function with estimated GFR<45 ml/min/1.73 m².

Furthermore patients include those with stable single RAS blockadebackground therapy (i.e. either ACE-inhibitor or ARB with unchangeddaily dose.

The composite primary endpoint of the study is time to the firstoccurrence of any of the following components:

-   -   CV death        -   sustained decrease of 40% or more in eGFR (CKD-EPI)cr        -   incidence of ESRD defined by either        -   continuous renal replacement therapy (dialysis or renal            transplantation) or        -   sustained eGFR<15 ml/min/1.73 m² for patients with baseline            eGFR≥30 ml/min/1.73 m² or eGFR<10 ml/min/1.73 m² for            patients with baseline eGFR<30 ml/min/1.73 m²

A secondary endpoint is defined as time to the first occurrence of anyof the following components: Occurrence of

All-cause mortality or all-cause hospitalization

All-cause hospitalization

All-cause mortality

eGFR (CKD-EPI)cr slope of change from baseline

Other secondary endpoints are any one of the following components:

-   Time to CV death confirmed by adjudication-   Time to first occurrence of sustained decrease of 40% or more in    eGFR confirmed by adjudication-   Time to first incidence of ESRD confirmed by adjudication-   Time to first hospitalization for congestive heart failure confirmed    by adjudication-   Time to first all-cause hospitalization-   Time to all-cause mortality-   Time to first 3-MACE (i.e. CV death, non-fatal MI, non-fatal stroke)    confirmed by adjudication-   Time to first occurrence of all-cause mortality, sustained decrease    of 40% or more in eGFR or incidence of ESRD confirmed by    adjudication-   Time to first occurrence of all-cause mortality, sustained decrease    of 50% or more in eGFR or incidence of ESRD confirmed by    adjudication-   Time to first occurrence of all-cause mortality, sustained decrease    of 57% or more in eGFR or incidence of ESRD confirmed by    adjudication-   Time to first occurrence of composite renal endpoint (sustained    decrease of 40% or more in eGFR, incidence of ESRD) confirmed by    adjudication-   Time to first occurrence of composite renal endpoint 2 (sustained    decrease of 50% or more in eGFR, incidence of ESRD) confirmed by    adjudication-   Time to first occurrence of composite renal endpoint 3 (sustained    decrease of 57% or more in eGFR, incidence of ESRD) confirmed by    adjudication-   Time to first sustained decrease of 57% or more in eGFR confirmed by    adjudication-   Time to first sustained decrease of 50% or more in eGFR confirmed by    adjudication-   Time to first sustained decrease of 30% or more in eGFR confirmed by    adjudication-   Time to first incidence of acute renal failure (incl. AKI) confirmed    by adjudication-   Time to first incidence of AKI confirmed by adjudication-   Time to onset of DM (defined as HbA1c≥6.5% or as diagnosed by the    Investigator) in patients without DM defined as no history of DM and    HbA1c<6.5% at baseline

Example 1B: Treatment of Patients with Chronic Kidney Disease

Empagliflozin is administered to patients in a randomised, double-blind,placebo controlled, parallel group study to compare treatment withempagliflozin 10 mg once daily with placebo as add-on therapy tostandard of care in patients with chronic kidney disease. The durationof the patients is preferably a long term treatment, for example between30 and 48 months.

Patients include individuals with presence of chronic kidney diseasewith high risk of cardiorenal events defined by at least one of thefollowing:

-   -   A) Impaired renal function with estimated GFR≥20 and <45        ml/min/1.73 m² or    -   B) Estimated GFR≥45 and <90 ml/min/1.73 m² and very high levels        of albuminuria (i.e. macroalbuminuria) defined as UACR 200 mg/g        creatinine

Furthermore patients include those with a clinically appropriate dose ofsingle agent RAS blockade background therapy (i.e. either ACE-inhibitoror ARB). Those participants for whom RAS blockade is not consideredindicated (e.g. due to concomitant medication or co-morbidity), or whocannot tolerate RAS blockade will still be eligible to enter the trial,but the reason for not using RAS blockade will be documented.

The composite primary endpoint of the study is time to the firstoccurrence of any of the following components:

-   -   CV death    -   Renal disease progression        -   sustained decrease of 40% or more in eGFR (CKD-EPI)cr        -   sustained eGFR<10 ml/min/1.73 m²        -   Incidence of ESRD defined by continuous renal replacement            therapy (by either dialysis or renal transplantation) or        -   renal death

The key secondary endpoint is defined as time to the first occurrence ofany of the following components: Occurrence of

-   -   Cardiovascular death or hospitalization for heart failure;    -   Hospitalization from any cause; and    -   All-cause mortality.

Other secondary outcomes which will include the individual components ofthe primary composite outcome:

-   -   Renal disease progression (as defined above);    -   Cardiovascular death.

Tertiary assessments will involve intention-to-treat analyses among allrandomized participants of the effects of allocation to empagliflozinversus placebo during the scheduled treatment period on:

-   -   Renal disease progression, overall and with ESRD and a sustained        ≥40% decline in eGFR considered separately;    -   Annual rate of change in eGFR, overall and separately from 2        months, in all participants and separately in various        subdivisions (as specified below);    -   Mortality from particular categories of causes, including        cardiovascular (e.g. coronary death, sudden cardiac death [not        know to be coronary], heart failure, other cardiac, stroke, and        other vascular) and non-cardiovascular (e.g. renal, infection,        cancer, other medical, and non-medical) causes;    -   The primary outcome composite and separately, the annual rate of        change in GFR, in various subdivisions based on assessments made        at the Randomization visit:        -   (a) History of prior disease (presence vs. absence):            diabetes mellitus*; cardio-vascular disease; heart failure;            peripheral arterial disease;        -   (b) Participant characteristics: age, sex, region, blood            pressure, body mass index;        -   (c) Laboratory values: HbA1c; eGFR; urinary            albumin:creatinine ratio; haematocrit;        -   (d) Medication: RAS blockade; beta-blocker; diuretics;    -   Major cardiovascular events (defined as the composite of        cardiovascular death, myocardial infarction, stroke or        hospitalization for heart failure);    -   New-onset diabetes mellitus (defined as clinical diagnosis,        commencement of glucose-lowering treatment, or central HbA1c≥48        mmol/mol on at least one occasion) among participants without        diabetes at baseline*, overall and separately among those with        normoglycaemia or “pre-diabetes” (defined as HbA1c<39        [normoglycaemia] or ≥39 to <48 mmol/mol [pre-diabetes],        respectively). *Diabetes at baseline is defined as        patient-reported history of diabetes, use of glucose-lowering        medication or baseline HbA1c≥48 mmol/mol at Randomization visit.

Example 2: Pharmaceutical Composition and Dosage Form

The following example of solid pharmaceutical compositions and dosageforms for oral administration serves to illustrate the present inventionmore fully without restricting it to the contents of the example.Further examples of compositions and dosage forms for oraladministration, are described in WO 2010/092126. The term “activesubstance” denotes empagliflozin according to this invention, especiallyits crystalline form as described in WO 2006/117359 and WO 2011/039107.

Tablets containing 2.5 mg, 5 mg, 10 mg or 25 mg of the active substanceempagliflozin. Amounts of the ingredients are provided in mg perfilm-coated tablet.

Active substance 2.5 mg/ 5 mg/ 10 mg/ 25 mg/ per tablet per tablet pertablet per tablet Wet granulation Empagliflozin 2.5000 5.000 10.00 25.00Lactose 40.6250 81.250 162.50 113.00 Monohydrate Microcrystalline12.5000 25.000 50.00 40.00 Cellulose Hydroxypropyl 1.8750 3.750 7.506.00 Cellulose Croscarmellose 1.2500 2.500 5.00 4.00 Sodium PurifiedWater q.s. q.s. q.s. q.s. Dry Adds Microcrystalline 3.1250 6.250 12.5010.00 Cellulose Colloidal silicon 0.3125 0.625 1.25 1.00 dioxideMagnesium stearate 0.3125 0.625 1.25 1.00 Total core 62.5000 125.000250.00 200.00 Film Coating Film coating system 2.5000 4.000 7.00 6.00Purified Water q.s. q.s. q.s. q.s. Total 65.000 129.000 257.00 206.00

Details regarding the manufacture of the tablets, the activepharmaceutical ingredient, the excipients and the film coating systemare described in WO 2010/092126, in particular in the Examples 5 and 6,which hereby is incorporated herein in its entirety.

1. A method of treating, reducing the risk of or slowing the progressionof chronic kidney disease in a patient with chronic kidney disease, saidmethod comprising administering empagliflozin to the patient.
 2. Themethod of claim 1, wherein the method additionally reduces the risk ofcardiovascular death in the patient.
 3. The method of claim 1, whereinthe method additionally reduces the risk of all-cause mortality in thepatient.
 4. The method of claim 1, wherein the method additionallyreduces the risk of all-cause hospitalization in the patient.
 5. Themethod of claim 1, wherein the patient has moderately to severelydecreased renal function.
 6. The method of claim 1, wherein the patienthas elevated albuminuria levels ≥200 mg/g.
 7. The method of claim 1,wherein the patient has an eGFR≥20 to <45 mL/min/1.73 m².
 8. The methodof claim 1, wherein the patient has an eGFR≥20 mL/min/1.73 m² and aurinary albumin-to-creatine ratio (UACR)≥200 mg/g.
 9. The method ofclaim 1, wherein the patient has an eGFR≥45 and <90 ml/min/1.73 m² and aurinary albumin-to-creatine ratio (UACR)≥200 mg/g.
 10. The method ofclaim 1, wherein the patient is treated with a RAAS inhibitor.
 11. Themethod of claim 1, wherein the patient is treated with anAngiotensin-Converting Enzyme (ACE) inhibitor and/or an angiotensin IIreceptor blocker (ARB).
 12. The method of claim 1, wherein the patientis a non-diabetic patient.
 13. The method of claim 1, wherein thepatient is a non-diabetic and non-pre-diabetic patient.
 14. The methodof claim 1, wherein the patient is a patient with pre-diabetes or apatient with type 2 or type 1 diabetes mellitus.
 15. The method of claim1, wherein empagliflozin is administered at a dose in a range from 1 mgto 25 mg.
 16. The method of claim 1, wherein empagliflozin isadministered at a dose of 10 mg or 25 mg.
 17. The method of claim 1,wherein empagliflozin is administered once daily to the patient.